tbuckley/cabot-search huggingface dataset:
Use of circulating tumor DNA (ctDNA) for early assessment of treatment response in patients with advanced colorectal cancer (aCRC): A real-world (RW) analysis.
Authors: Pashtoon Murtaza Kasi, Caroline Weipert, Tim Nguyen, Jiemin Liao, Nicole Zhang, Shaun Forbes, Sean Gordon, Benjamin R. Tan
Journal: Journal of Clinical Oncology (2023)

246 Background: Data suggests that changes in ctDNA quantity correlate with response to therapy in patients with advanced solid malignancies. However, there is little consistency on how to calculate and interpret such changes. Here, we apply a clinically-validated molecular response algorithm to a RW cohort of patients with aCRC to further evaluate its ability to assess treatment outcomes. Methods: We queried the Guardant INFORM database, which comprises aggregated commercial payer health claims and de-identified records from patients with comprehensive ctDNA testing via Guardant360 (G360) from September 2018-March 2022. Patients with aCRC who received G360 within 15 weeks prior to new treatment initiation (any line of therapy) and a second test 3-15 weeks after treatment initiation were retrospectively evaluated using the G360 Response algorithm. Cox proportional hazards (CPH) were used for RW time to next treatment (TTNT), time to treatment discontinuation (TTD), and overall survival (rwOS) analyses. Patients categorized as molecular responders had a &gt;50% decrease in mean variant allele fraction (VAF) ratio from pre-treatment to on-treatment. Gender, age, line of therapy (LOT) and comorbidities were included as covariates. Median TTNT, TTD, and rwOS were calculated by Kaplan Meier. Results: Of 185 aCRC patients with eligible MR results, 65% received chemotherapy +/- VEGF, 21% received regimens containing anti-EGFR monoclonal antibodies, and 14% received other therapies. 43% of aCRC patients were classified as molecular responders, 42% were non-responders, and 15% were not evaluable by the algorithm due to no/low ctDNA at one or both timepoints. 16% of patients cleared their ctDNA on treatment (i.e., ctDNA became undetectable). Molecular responders had significantly longer TTNT (median 10.1 months vs 6.1 months; HR p &lt; 0.005), TTD (median 5.2 Months vs 3.9 months, HR p=0.041), and rwOS (not reached vs 17.8 months, HR p=0.017). Conclusions: Patients with aCRC classified as molecular responders, as calculated by this algorithm, had prolonged time on treatment and overall survival. Compared to tumor markers, ctDNA has a short half-life, which can allow for early response assessment, as shown by our study. These findings are relevant for clinical care, with future potential to allow for adaptive clinical trial design. [Table: see text]
Evaluation of chromatin remodelers in pancreatic neuroendocrine neoplasms.
Authors: Salma Ferosh Usman Khan, Rajni Yadav, Nihar Ranjan Dash, Sujoy Pal, Prasenjit Das, Anand Narayan, V P Jyotsna, Shamim Ahmed Shamim, Sameer Rastogi, Shipra Agarwal, Mehar C Sharma
Journal: Journal of Clinical Oncology (2023)

652 Background: Pancreatic neuroendocrine neoplasms (PanNENs) are rare entities comprising 1-2% of gastroenteropancreatic neoplasms with an annual incidence of 0.48/100,000 population in the world. The molecular pathways underpinning the entity are less explored owing to its rarity. We aimed to analyse and correlate the expression of chromatin remodelers in PanNENs from Indian subcontinent. Methods: An ambispective study (prospective 2014-2018 as well as retrospective 2018-2021) was conducted. Haematoxylin and eosin stained slides with immunohistochemistry slides (chromogranin, synaptophysin) of 73 cases of PanNENs were retrieved from archives of Department of Pathology, AlIMS, New Delhi and evaluated for assessment of histopathological parameters. Following slide review, grading and staging were done based on WHO 2017 Classification and AJCC eighth edition respectively. Representative formalin fixed paraffin embedded block was selected after slide review and retrieved for performing immunohistochemical staining with antibodies against ATRX, DAXX, SETD2, H3K36Me3 and ARID1A using Ultra Vision Quanto polymer detection system by Thermo Fisher Scientific. Data was analysed using STATA version SE14. Results: Study cohort of 73 PanNENs had a mean age of presentation 41 years (Range: 8 years -70 years) and male to female ratio of 1.43:1. Majority of the tumors in our study were non functional (63.01%). Loss of nuclear expression of ATRX/DAXX (at least one marker) was seen in 26/73 (35.62%) cases. Loss of expression had significant correlation with pathological stage of the tumor, presence of distant metastasis and adverse prognostic outcome (p value-&lt;0.05). Lower grade tumors with low to intermediate ki67 index had higher preponderance for loss of expression of ARID1A. Loss of expression of any of the chromatin remodelers (ATRX/DAXX/ARID1A/H3K36Me3) was noted in 44/73 cases (60.27%) and was more frequently associated with advanced stage of tumor or recurrence/metastasis/death (p value-0.005). Conclusions: Loss of chromatin remodelers such as ATRX, DAXX, ARID1A, SETD2 and H3K36ME3 is involved in the pathogenesis of pancreatic neuroendocrine neoplasms and are associated with adverse outcomes, so loss or lower immunohistochemical expression for these can serve as a poor prognostic factor and guide for adjuvant therapy.
Adjuvant transarterial chemoembolization with sorafenib for patients with hepatocellular carcinoma with portal vein tumor thrombus after surgery: A phase III, multicenter, randomized, controlled trial.
Authors: Ming Kuang, Zhenwei Peng, Wenzhe Fan, Zelong Liu, Han Xiao, Jianfei Tu, Rong Tang, Zhen Huang, Yu Cheng, Fuliang Li, Mingjian Lu, Jiaping Li
Journal: Journal of Clinical Oncology (2023)

493 Background: To compare the efficacy and safety of sorafenib plus transarterial chemoembolization (SOR-TACE) versus sorafenib alone as postoperative adjuvant therapy for hepatocellular carcinoma (HCC) patients with portal vein thrombus (PVTT). Methods: This was a phase III, multicenter, randomized, control clinical trial. Eligible HCC patients with PVTT were included and randomly assigned (1:1) to receive SOR-TACE or sorafenib alone as postoperative adjuvant therapy. Sorafenib treatment was started within 3 days after randomization, with an initial dose of 400mg twice a day. In the SOR-TACE group, TACE was performed one day after the administration of sorafenib. The primary endpoint was recurrence-free survival (RFS). Results: From October 2019 to March 2022, a total of 158 HCC patients with PVTT from China were enrolled and randomized. After a median follow-up duration of 28.4 months, the median RFS was significantly longer in the SOR-TACE group (16.8 vs. 12.6 months; hazard ratio, 0.57; P = 0.002). The median overall survival (OS) was also significantly longer with SOR-TACE than with sorafenib (30.4 vs. 22.5 months; hazard ratio, 0.57; P = 0.017). Multivariable analysis indicated SOR-TACE treatment was an independent risk factor for both RFS and OS. The SOR-TACE group did not show additional toxicity compared with the sorafenib alone group. Conclusions: The combination of sorafenib and TACE as postoperative adjuvant therapy in HCC patients with PVTT resulted in longer RFS and OS compared to sorafenib alone and was well tolerated. Clinical trial information: NCT04143191 .
Development of a postoperative nomogram to predict overall survival in gastric cancer using variables the AJCC recommends for collection and registration.
Authors: Etsuro Bando, Xinge Ji, Michael W. Kattan, Yusuke Koseki, Kenichiro Furukawa, Keiichi Fujiya, Yutaka Tanizawa, Masanori Terashima
Journal: Journal of Clinical Oncology (2023)

468 Background: The American Joint Committee on Cancer (AJCC) has increasingly recognized the need for individual risk prediction model for the era of tailored therapy. This study aimed to develop a postoperative gastric cancer nomogram for prediction of overall survival (OS). Methods: The nomogram was developed using data of 4,990 patients with primary gastric cancer who underwent macroscopically complete resection (residual tumor: R0 or R1) at Shizuoka Cancer Center (Shizuoka, Japan), and it was created with a multivariable Cox proportional hazard regression model. Fifteen pathological or host-related variables (age, sex tumor location, tumor size, macroscopic type, histology, depth (pT), number of positive nodes (pN), number of negative nodes, location of positive nodes, lymphovascular invasion, lavage cytology (CY), tumor margin, serum CEA and serum CA19-9) were collected. They are recommended to collect and register by the AJCC. The model was validated internally using measures of discrimination (Harrell’s C-index), calibration and decision curve analysis. A stage-specific subset survival analysis of the three risk groups (low, intermediate, high) calculated using the nomogram was performed. Results: In the development procedure, multivariable analysis for OS selected 11 variables for constructing the nomogram. The developed nomogram showed good discrimination, with a C-index of 0.812; that of the American Joint Committee on Cancer (AJCC) pathological stage was 0.756. The nomogram performed well in the calibration and decision curve analyses. A stage-specific subset survival analysis of the three risk groups calculated using the nomogram also showed the superiority of nomogram-prediction when compared to AJCC ordinal staging. Conclusions: This new postoperative risk model accurately predicts OS in gastric cancer and can be used for patient counseling in clinical practice and clinical trial eligibility determination.
Disparities and outcomes in young adults admitted for gastric cancer in the US.
Authors: Rafaella Litvin, Vaishali Deenadayalan, Muhammad Bilal Ibrahim, Michelle Ishaya
Journal: Journal of Clinical Oncology (2023)

298 Background: Although global incidence of gastric cancer has been decreasing over the past decades, an upward trend has been reported in younger patients and certain ethnic groups over the past few years. The reason for this epidemiological trend is not fully understood, but differences in presentation and prognosis suggest that gastric cancer in the young might represent a different clinical entity. Here, we seek to identify differences in demographic characteristics and outcomes between young adults and older patients admitted for gastric cancer. Methods: Using the National Inpatient Sample (NIS) database, we identified all adult patients admitted primarily for gastric cancer from 2016 to 2019. We analyzed demographic characteristics of young adults (defined as those aged between 20 and 49-years-old) and older patients (aged 50 and above) as well as differences in in-hospital mortality, total hospital charges, and length of stay. Multivariate logistic regression analysis was conducted to adjust for confounders. Results: During the period studied, 77,720 patients were admitted with gastric cancer, of which 9,650 (12.4%) were young adults and 68,115 (87.6%) were old individuals. Young adults were more likely to be female (42.4 vs. 35.6%, p &lt; 0.01). Hispanics comprised 30.9% of admissions for gastric cancer of young adults (vs. 15% in older adults p-value &lt;0.01). Young adults were also over 3 times more likely to be uninsured than older individuals (9.6 vs. 2.6%, p-value &lt;0.01) and more likely to be cared for in urban (98.2 vs. 96.2%, p &lt; 0.01) and teaching (85.4 vs. 80.8%, p &lt; 0.01) hospitals. Young adults had longer lengths of stay and lower hospital charges (see table). No difference was found in mortality, despite a lower comorbidity burden in young adults based on the Charlson Comorbidity Index, possibly due to young adults being candidates for more aggressive therapy and having more aggressive disease. Conclusions: The higher incidence of gastric cancer in Hispanic and uninsured young adults poses a complex public health issue, especially in the context of recent research suggesting more aggressive disease in this population. The reported findings likely reflect both a shift in the U.S. population over the years as well as a rising incidence among Hispanic young adults. It is important to increase awareness of these epidemiological disparities. Further research is needed to determine whether establishing screening programs for gastric cancer in certain populations might be beneficial in the U.S. [Table: see text]
Depth of response in patients with locally advanced pancreatic cancer treated with modified FOLFIRINOX or gemcitabine plus nab-paclitaxel combination therapy: An exploratory subgroup analysis of JCOG1407.
Authors: Taro Shibuki, Masafumi Ikeda, Masato Ozaka, Satoshi Kobayashi, Akihiro Ohba, Akiko Todaka, Kohei Uemura, Yusuke Sano, Yoshiki Horie, Yusuke Kumamoto, Kazuhiko Shioji, Masashi Kanai, Tomohiro Nishina, Takehiro Okabayashi, Nao Fujimori, Akio Katanuma, Yukiko Takayama, Hidetaka Tsumura, Junji Furuse, Makoto Ueno
Journal: Journal of Clinical Oncology (2023)

746 Background: Depth of response (DpR; max% reduction from baseline in sum of target lesion diameters), has been reported to be associated with improved prognosis in several malignancies. However, there have been few reports regarding DpR in patients with locally advanced pancreatic cancer (LAPC). Thus, we investigated the association between DpR and overall survival (OS), and whether there were any differences in treatment efficacy on DpR between modified FOLFIRINOX (mFFX) versus gemcitabine plus nab-paclitaxel (GnP) as 1st-line chemotherapy for LAPC, using the results from JCOG1407 which was a randomized phase II trial comparing these regimens. Methods: Of the 126 patients enrolled in JCOG1407, patients were eligible except for the followings; patients who never had an imaging study or had only non-target lesions. The association between DpR and OS was investigated by dividing DpR into 3 groups at the tertile point (T1, T2 and T3 from largest to smallest), and whether DpR contributes to OS was examined by multivariable analysis. The differences in treatment efficacy between both regimens were investigated byevaluating DpR, time to DpR, and duration of response (DoR). Results: A total of 109 patients were eligible for this study (n = 53/56 in mFFX/GnP). The number of patients in T1, T2, and T3 were 37, 36, and 36, respectively. The median OS of T1, T2, and T3 were 29.3 (95% CI, 21.0-NE), 20.6 (95% CI, 15.8-24.5), and 19.0 months (95% CI, 12.7-22.4), respectively ( P= 0.0237). Multivariable analysis identified DpR as an independent prognostic factor for OS (HR 1.883, 95% CI 1.030-3.442, P= 0.040 for T2 vs. T1, and HR 2.523, 95% CI 1.342-4.744, P= 0.004 for T3 vs. T1). The median DpR in GnP was better than that in mFFX (28.9 vs. 22.7%; P= 0.041). The median DoR in mFFX tended to be longer compared to that in GnP (8.2 vs. 5.3 months; P= 0.132). No differences in mean time to DpR were observed between the two regimens. Conclusions: In LAPC patients receiving 1st-line chemotherapy, larger DpR contributed to OS. Although OS and PFS between mFFX and GnP were similar, the treatment efficacy on DpR and DoR might be different between the two regimens. Clinical trial information: UMIN000023143 .
Pathological features associated with lymph node disease in patients with appendiceal neuroendocrine tumors.
Authors: Salvador Rodriguez Franco, Madeline Thomas, Andrii Khomiak, Lia Roque Assumpcao, Toshitaka Sugawara, Camille Stewart, Richard D. Schulick, Marco Del Chiaro, Steven Ahrendt, Ana Gleisner
Journal: Journal of Clinical Oncology (2023)

238 Background: Appendiceal neuroendocrine tumors (ANETs) are well known for their benign and slow progression; nonetheless, the presence of lymph node metastasis has been described in up to 50% of all cases. The risk of metastasis is mainly associated with tumor size, and the role of other pathological features remains unclear. Hence, this study was designed to assess the pathologic features of ANETs associated with an increased risk of lymph node metastasis. Methods: Patients ≥18yrs of age with ANETs were identified in the National Cancer Database (NCDB) from 2004 to 2017. Groups were defined based on lymph node status as N(-) (all examined nodes were negative) and N(+) (one or more examined nodes were positive). Multivariable models using demographics and oncological features were used to identify factors independently associated with nodal metastasis (N+). Marginal effects, specifically for tumors &lt;2 cm were also calculated. Results: A total of 2,465 cases were identified and included for data analysis. Among these, 23% had lymph node metastases, including 33 of 979 tumors &lt;1 cm (3.4%), and 145 of 696 tumors ≥1 cm but ≤2 cm (20.8%). Tumor size, depth of tumor invasion, and presence of lymphovascular invasion (LVI) were identified as independent predictors of lymph node metastasis (p &lt;0.001). When evaluating marginal effects, both the depth of tumor invasion and the presence of LVI were associated with increased risk of node metastasis in small tumors (&lt;2 cm), comparable to the mere risk of node metastasis in big tumors (≥2cm). In addition, for small ANETs (&lt;2cm), the true positive rates (TPR) of node metastasis vary according to the number of assessed lymph nodes, differing significantly between patients with at least 12 evaluated lymph nodes vs. those with less than 12 (TPR 4.7% vs. 1.6% for &lt;1 cm [p =0.02], and 40.1% vs. 25.7% in ≤2 cm ANETs, [p &lt;0.001]). Conclusions: In ANETs, the presence of high-risk pathological features, including LVI and tumor depth, increases the risk of node metastasis in addition to tumor size, and should be considered when selecting the optimum management and follow-up in these patients. [Table: see text]
The tumor mutation burden in gastro-entero-pancreatic-neuroendocrine tumors.
Authors: Sun Young Jeong, Seung Tae Kim, Jae Yeon Jang
Journal: Journal of Clinical Oncology (2023)

654 Background: Neuroendocrine tumors (NET) are rare tumors with limited treatment options. Tumor mutation burden (TMB) has been known as a novel biomarker in various tumor types. However, there has been little study of the role of TMB-high in gastro-entero-pancreatic (GEP)-NETs. Methods: We analyzed 31 metastatic GEP-NET patients who were newly diagnosed between 2013 to 2022. Next-generation sequencing (NGS) including TMB analysis, as a routine clinical practice was performed. The TruSight Oncology 500 assay from Illumina was used as a cancer panel. Results: Among a total of 31 patients, the median TMB was 4.7 mutation/Mb (3.10-6.3). Primary origin was stomach in 4 (12.9%), small bowel in 2 (6.5%), rectum in 7 (22.6%), pancreas in 21 (38.7%), bile duct in 1 (3.2%), gall bladder in 4 (12.9%), liver in 1 (3.2%) patient. 17 (54.8%) patients were diagnosed with well-differentiated NET with grade 1 in 3 (9.7%), and grade 2 in 14 (45.2%) patients. Grade 3 NET (neuroendocrine carcinoma) was confirmed in 14 (45.2%) patients. The median number of metastases was 2.7 (1.0-4.0). The most common metastatic site was the liver (26 patients, 83.9%). All tumors were classified as type of micro-satellite stable (MSS). Only one patient had the tumor with high TMB (266.4 mutation/Mb). This tumor was classified as the grade 3 neuroendocrine carcinoma and the primary tumor site was pancreas. Conclusions: This analysis revealed that the GEP-NETs were generally considered as tumor-type of low TMB. However, uncommonly, GEP-NET with high-TMB could be found. For the precision medicine, the NGS test is needed as a routine clinical practice in this tumor type.
Analysis of plasma circulating tumor DNA in borderline resectable pancreatic ductal adenocarcinoma treated with neoadjuvant modified FOLFIRINOX: Clinical relevance of DNA damage repair gene alterations.
Authors: Dong-Hoon Lim, Jaewon Hyung, Sang Soo Lee, Jae Ho Jeong, Baek-Yeol Ryoo, Kyu-Pyo Kim, Changhoon Yoo
Journal: Journal of Clinical Oncology (2023)

737 Background: There is no reliable biomarker to guide treatment for patient with borderline resectable pancreatic ductal adenocarcinoma (PDAC) treated with neoadjuvant modified (m)FOLFIRINOX. We investigated the role of plasma circulating tumor DNA (ctDNA) sequencing to discover potential biomarkers for patients treated with neoadjuvant mFOLFIRINOX in our phase 2 clinical trial (ClinicalTrials.gov identifier: NCT02749136). Methods: Among 44 patients enrolled in the trial, patients with plasma ctDNA analysis performed at baseline or post-operative period were included in the analysis. Plasma cell-free DNA isolation and sequencing of ctDNA were performed using the Guardant 360 assay. Association of clinical outcomes with germline or somatic mutations of DNA damage repair (DDR) genes was analyzed. Somatic alterations other than DDR genes were also analyzed to find potential biomarkers of neoadjuvant mFOLFIRINOX. Progression free-survival (PFS) was defined as time from the initiation of mFOLFIRINOX to disease progression or any cause of death. Overall survival (OS) was defined as the time from the initiation of mFOLFIRINOX to any cause of death. Results: Among 44 patients, 28 patients had ctDNA sequencing data qualified for the analysis and were included in this study (15 patients with baseline data only, 3 patients with post-operative data only, and 10 patients with both baseline and post-operative data). Median age was 59 (range, 41-73) years and 15 patients (53.6%) were male. Among 25 patients with baseline plasma ctDNA data, 11 patients (44%) had somatic or germline alteration of DDR genes detected at baseline including ATM, BRCA1, BRCA2 and MLH1, and showed significantly better PFS than those without such DDR gene alterations (median 26.6 vs. 13.5 months, log-rank p = 0.004). Although there was a trend for better OS in patients with DDR gene alterations, this was not statistically significant (log-rank p = 0.29). The most observed baseline somatic alteration was TP53 (n = 7, 28%), followed by KRAS (n = 6, 24%). Patients with somatic KRAS mutation at baseline had significantly worse OS (median 8.5 months vs. not applicable, log-rank p = 0.003) than those without. Among 13 patients with post-operative plasma ctDNA data, 8 patients (61.5%) had detectable somatic alterations. Conclusions: Detection of germline or somatic mutations of DDR genes from plasma ctDNA at baseline was associated with better survival outcomes of patients with borderline resectable PDAC treated with neoadjuvant mFOLFIRINOX. Detection of DDR gene alterations from plasma ctDNA may have a potential role as biomarker for prognosis in patients with borderline resectable PDAC treated with mFOLFIRINOX.